TB therapeutic drug monitoring – analysis of opportunities in Romania and Ukraine

INTRODUCTION: Therapeutic drug monitoring (TDM) could improve TB treatment outcomes by avoiding drug toxicity or underdosing. In this study, we describe the patient burden in three TB centres in Romania and Ukraine with a TDM indication, as per the current guidelines, in order to estimate the feasibility of implementing TDM. METHODS: A retrospective multi-centre study was conducted at the Iasi Lung Hospital (Iasi, Romania), Bucharest Marius Nasta Institute (Bucharest, Romania) and Chernivtsi TB Centre (Chernivtsi, Ukraine) in adult hospitalised TB patients. RESULTS: A total of 927 participants were admitted, of whom 37.8% had at least one indication for TDM, the most frequent being slow response to TB treatment (202/345, 58.6%); 55.5% had at least one cavity present on chest X-ray. Patients with a TDM indication stayed in the hospital for a median of 67 days and took on average 2 months more to reach a successful TB outcome. CONCLUSION: TDM could be a valuable tool to improve management of selected TB patients. The decision on whether to perform TDM is often delayed by 2 months due to waiting for culture results after treatment initiation. A randomised control trial should be performed in order to define TDM’s precise role in TB therapy.

most frequent being slow response to TB treatment (202/345, 58.6%); 55.5% had at least one cavity present on chest X-ray.Patients with a TDM indication stayed in the hospital for a median of 67 days and took on average 2 months more to reach a successful TB outcome.
C O N C L U S I O N : TDM could be a valuable tool to improve management of selected TB patients.The decision on whether to perform TDM is often delayed by 2 months due to waiting for culture results after treatment initiation.A randomised control trial should be performed in order to define TDM's precise role in TB therapy.K E Y W O R D S : personalised; patient-centred; hospital; diagnosis; treatment TB remains one of the most globally impactful infectious diseases, with a mortality of 1.3 million in 2020.Global average treatment success rates are 86% for drug-susceptible TB (DS-TB) and 59% for multidrugresistant TB (MDR-TB). 1Suboptimal treatment success rates have been linked to several factors, either those related to case severity or to the treatment itself.In the former category, TB management can be complicated by various factors, such as comorbidities (e.g., HIV or diabetes mellitus [DM]), differences in lifestyle (e.g., alcohol consumption, smoking) and TB severity (e.g., the presence of cavities).In the latter, the already complex and lengthy treatment can be further impaired by low or high drug exposures. 2In this context, therapeutic drug monitoring (TDM) is a promising tool, as it can help with clinical decision-making by offering accurate measurements of drug concentrations allowing clinicians to make informed decisions on drug dosing. 35][6][7] Those living with HIV, those diagnosed with advanced kidney disease, DM and patients with DR-TB are considered at-risk patients.
Romania has the highest TB burden within the European Union (EU), accounting for a fourth of all TB cases in the EU, 8 while Ukraine, bordering Romania to the north, is one of the top 30 countries with the highest TB burden, especially for MDR-TB. 9uidelines in both countries recommend admitting patients with TB disease at least for treatment initiation, ideally until culture negativity. 10 Due to its high implementation costs and the lack of familiarity among clinicians and national stakeholders with this technique, TDM is currently not part of routine care in these settings.Furthermore, despite a large body of knowledge on the optimum plasma concentrations of TB drugs, 11 there are gaps in the information about implementing TDM in resource-scarce settings at the community level. 3To facilitate the future implementation of TDM strategies, it is crucial to obtain estimates of patients with a TDM indication.These estimates will serve as a fundamental basis for conducting comprehensive cost-effectiveness studies.
In this study, we describe the patient burden in three TB centres in Romania and Ukraine with a TDM indication as per the current guidelines.

Design and setting
A retrospective multi-centre study was conducted in the Iasi Lung Hospital (Iasi, Romania), Bucharest Marius Nasta Institute (Bucharest, Romania) and Chernivtsi TB Centre (Chernivtsi, Ukraine).
The Iasi Lung Hospital is the regional TB centre for the north-eastern region of Romania.The Marius Nasta Institute is the national Romanian TB expertise centre.Chernivtsi TB Centre, a specialist TB centre, is located in the Chernivetska Oblast, in south-western Ukraine.Inclusion criteria were hospitalised adult patients (aged >18 years) diagnosed with TB of any form, who initiated treatment between 1 January 2019 and 31 December 2020, and had both renal function and liver enzymes measured at least once during or at start of TB treatment.Hospitalised TB patients in all centres have documented diagnosis data, known HIV status and chronicled hospitalisation data.Other comorbidities were either documented (e.g., glycated haemoglobin levels for DM) or derived from medical history.

Data collection and storage
Patient-and disease-related data were extracted from medical records and captured in Research Electronic Data Capture (REDCap) v11.0.3 (Vanderbilt University, Nashville, TN, USA), a secure web-based platform.Data extraction was verified by another investigator.Data collection mistakes were corrected and again verified by another investigator.After completion of data collection, IM performed a final random check of all collected data.Data collection included general demographics, smoking and alcohol consumption, and known comorbidities at the time of TB diagnosis.Diagnosis data included symptoms, chest X-ray interpretation and results from direct microscopy of sputum and culture of sputum or other biological material.Baseline admission data included treatment programme and hepatic and renal laboratory tests at baseline.Hospitalisation data included laboratory parameters, adverse events (AEs) and management of hepatic or renal toxicity.TB treatment outcome was collected using WHO-defined TB outcomes (time to culture conversion in months, total duration of treatment, treatment success, loss to follow-up, death). 1 For each patient, indications for TDM were collected.TDM indications as listed in the guidelines were as follows: 12,13 slow response to TB treatment (culture conversion beyond 2 months for DS-TB and 4 months for MDR-TB), severe gastro-intestinal abnormalities (severe gastroparesis, short bowel syndrome, chronic diarrhoea with malabsorption), impaired renal clearance (defined as glomerular filtration rate <60 ml/min/1.73m 2 , CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) or acute kidney failure (drop in estimated glomerular filtration rate [eGFR] of at least 50%), comorbidities (HIV infection, DM type 2) and use of second-line TB medication.Descriptive statistics were used to characterise the data set and the programme used was IBM SPSS v.27 (IBM, Armonk, NY, USA).All definitions of TB cases and outcomes follow the WHO framework.

General characteristics
Between 1 January 2019 and 31 December 2020, there were 927 TB patients admitted in all three centres.After excluding 19 patients due to the unavailability of documented follow-up data, 912 patients were included in the analysis: 378 in Iasi, 507 in Bucharest and 154 in Chernivtsi.The median age was 47 years (interquartile range [IQR] 35-61); 67.1% were male, 58.1% lived in rural areas, 48.1% were current smokers and 60.8% were current alcohol consumers.
More than a third of the patients (345/912, 37.8%) had at least one indication for TDM, 244/345 (70.7%) of whom had only one indication for TDM, 65 (18.8%)TB TDM in Romania and Ukraine had two and 36 had three or more (10.4%).The most frequently observed indication for TDM was slow response to TB treatment (202/345, 58.6%), followed by administration of second-line medication, including patients with DS-TB who were intolerant to one of the first-line drugs (92/345, 26.1%).Of the 92 participants, 72 (97.3%) had DR-TB (Figure ).

Description of the population with TDM indication
The three clinical sites were different in their proportion of patients with TDM indication, with Chernivtsi, Ukraine, having 125 patients with TDM indication out of 154 (81%), and sites in Romania having respectively 29.4% and 28.7% for Iasi and Bucharest.Sex, age or living situation (rural, urban, homeless) between the groups were comparable.Most (82%) were new TB patients, with the remainder being relapse cases.The majority had pulmonary TB (79.4%), with 9% presenting with a combination of lung and pleural TB.Regarding pulmonary TB diagnosis, 59.1% had bilateral involvement of the lungs, and 55.5% had at least one cavity present on pulmonary chest X-ray; 26.4% had sputum with >9 bacilli/field (þþþ) and 35.4% had culture result of >100 colonies (statistically significantly more than the group without TDM indication).
Patients with TDM indication stayed in the hospital for a median of 67 days (IQR 33.5-98), in contrast with patients without a TDM indication who stayed a median of 25 days (IQR 23-64).Increased liver enzymes were observed in 31.9% of the patients with TDM indication, with 7.3% having a >5 times elevation in aspartate transaminase levels.Overall, 19.4% had abnormal eGFR during hospitalisation, with 2.3% having acute kidney injury (defined by a decrease in eGFR of >50%).The time recorded for abnormal valuesboth hepatic and renalto improve and/or normalise was a median of 33 days (IQR 19-60), and 17.6% of patients with abnormal values did not experience a significant improvement, despite clinical measures taken, including supportive measures and changes in medication.
Side effects were reported in 24.6% of patients with TDM indication, the most frequent being gastrointestinal (e.g., nausea) in 7.8% of cases, while 2% presented with a severe allergic reaction.
Clinical measures taken to improve laboratory parameters or mitigate side effects included supportive treatment (3.5%), lowered dosages of TB drugs (4.4%), pausing TB medication for more than 7 days (4.6%).The clinical decision to stop and/or switch TB medication was made for 15.4% of patients with TDM indication (vs.for 0.7% in patients without TDM indication).The most frequently involved drugs were pyrazinamide, which was replaced by a fluoroquinolone (FQ), either levofloxacin or ofloxacin (8/25); the remainder of the cases on other first-line drugs were switched to an FQ, and in five cases to a combination drug, including an injectable drug (amikacin or kanamycin).
In terms of WHO TB outcomes, 86.6% of patients with TDM indication achieved treatment success; in patients without TDM indication, this was 88%.Death was recorded in 5.7% of patients with TDM indication and 6.7% of patients without TDM indication.Treatment duration was a median of 2 months longer for patients with TDM indication (8 months, interquartile range [IQR] 6-10 vs. 6 months, IQR 6-8) (Table ).

DISCUSSION
In this retrospective study conducted at three centres in Romania and Ukraine, where TDM is not currently part of routine practice, it was observed that over a third of the patients with TB disease would have a clear indication for TDM if this strategy were to be implemented.The most common criterion for TDM indication was a slow response to treatment.There were differences in the percentage of patients with TDM indication per centre: in Ukraine, 81.2% of hospitalised patients in 2019 had a TDM indication, whereas in Romania, this was 29.4% and 28.7%.This reflects, for example, the differences in the admitted patient populations, with Ukraine having the majority of the RR-TB cases.Furthermore, this could be attributed to differences in the base population of admission, where Ukraine has a lower income level than Romania, leading to a higher prevalence of RR-TB cases.In a resource-constrained setting, the decision to treat patients on an ambulatory basis is possibly more common, although this may deviate from national guideline recommendations.To note, the proportion of patients who achieved treatment success was comparable to patients without TDM indications, but the treatment duration was longer, likely due to guidelines recommending prolonged treatment based on delayed culture conversion.
Our study findings indicate that more than a third of patients (37.8%) were eligible for TDM according to the guidelines.Although the study sites were located in middle-income countries, another study with a similar methodology performed in Australia, showed that a similar proportion of patients (35%) were eligible for TDM. 14We speculate that this indicates that a significant proportion of patients would be eligible for TDM, irrespective of the setting.However, this observation also presents potential challenges when considering the feasibility of implementing TDM.
In our study, guideline TDM indicators may have led to the selection of clinically worse patients.This is congruent with current knowledge that patients with comorbidities and/or more TB symptoms are at higher risk of suboptimal treatment outcome or of developing adverse drug-related events.More than half (58.6%) of patients in our study were included due to the slow response to treatment, compared to only 9% in the previously mentioned Australian study, in which patients were more often selected based on comorbidities (e.g., DM).Factors influencing time to culture conversion in HIV-negative DS-TB patients include the presence of DM and extensive disease, smoking and alcohol consumption. 15In case of MDR-TB patients, one study concluded that the main risk factors for delayed culture conversion are high smear grade, smoking, alcohol consumption and ofloxacin resistance. 16In our study, patients with TDM indication consumed alcohol more frequently, had more comorbidities and tended to have more severe disease, with higher smear grade and worse culture results, bilateral lung involvement; also, a greater number had cavitary disease.However, as culture conversion depends on various clinical parameters, it should not be used alone to predict TB treatment effectiveness. 17Furthermore, in an international survey TB experts said that only 7% of those who perform TDM use slow response to treatment as a criterion for initiating TDM. 18uidelines recommend TDM if second-line drugs are used in the treatment programme, regardless of resistance status.Indeed, out of 92 patients who received second-line drugs, 20 had DS-TB and were treated with either an FQ and/or an injectable drug.0][21] TDM could help clinicians in both these cases.More robust studies are needed to clarify the benefits of TDM for FQ use in DS-TB. 22atients with TDM indication were hospitalised for a median duration of more than 2 months, while patients without TDM indications were discharged after 35 days.The national TB guidelines of Romania and Ukraine recommend hospitalisation until at least the patient is sputum-negative on microscopy, preferably until culture negativity. 23This indicates that patients with more severe disease, comorbidities and side effects tend to have prolonged hospital stays, primarily influenced by their specific medical condition.As previously mentioned, these findings strongly align with the TDM indications.Nevertheless, despite WHO TB outcomes not being statistically significantly different between the groups, patients with TDM indication stayed on treatment for a median of 2 months longer than patients without TDM indication, indicating that to achieve the same outcomes, more effort and resources had to be provided.Based on the higher additional costs per patient for extended hospitalisation in Romania (e4,363 euros) and Ukraine (e1,109 euros), 24,25 there is a potential economic benefit in addition to clinical benefit associated with treatment optimisation of these hospitalised patients.The implementation of TDM may be associated with higher costs, both in terms of the dedicated equipment required (e.g., high-performance liquid chromatography [HPLC]) and related consumables (assays) and the need for trained personnel.The willingness to implement TDM would be facilitated by additional evidence in favour TB TDM in Romania and Ukraine of cost-effectiveness.The evaluation of the impact of TDM should include strategies for identifying patient categories, facilitating data collection and analysis, e.g., from dried blood spots and saliva samples, and optimising the use of HPLC tools.By employing various TDM methods, such as dried blood spot and saliva samples, and strategically prioritising specific patients, TDM emerges as a potentially cost-effective intervention, especially in TB hospitals attached to university centres, which would have access to a HPLC machine from other departments.This would help to overcome one of the most important barriers to TDM implementation, which is the perceived large costs associated with this technique. 18Robust economic studies based on randomised clinical trials evaluating TDM are needed to clarify the cost-effectiveness of implementing TDM, especially in lower-income countries with high TB burdens.

Strengths and limitations
This large-scale retrospective study was conducted in three centres located within the European region, with a particular focus on Romania, which accounts for approximately one fourth of all TB cases reported in the EU/EEA (European Economic Area), and Ukraine, which has the fifth highest number of confirmed cases of XDR-TB in the world.The inclusion of Romania and Ukraine therefore adds significant relevance, given

CONCLUSION
This study, conducted in a high TB burden setting, shows that more than a third of TB patients are eligible for TDM according to current guidelines, most of whom are included because of slow response to treatment.In this context, the decision to perform TDM (Therapeutic Drug Monitoring) is often delayed due to the necessity of waiting for culture results, which are typically collected two months after the initiation of treatment.An alternative approach would be to start TDM after 1 or 2 weeks of treatment in those with risk factors for sub-optimal drug exposure, 5 e.g., patients with cavities, which would impair drug effectiveness due to the drug's poorer penetration in the cavities; however, this decision should be mindful of the resources available. 19,20The decision to implement TDM in a particular setting should take into account patient profiles, cost-effectiveness and potential benefits; a randomised controlled trial to further investigate the potential TDM opportunities in lowresource settings is thus warranted.Ceci est une etude r etrospective multicentrique a et e men ee a l'hôpital pulmonaire de Iasi (Iasi, Roumanie), a l'Institut Marius Nasta de Bucarest (Bucarest, Roumanie) et au centre antituberculeux de Chernivtsi (Chernivtsi, Ukraine) aupr es de patients adultes hospitalis es pour une TB.R É S U L T A T S : Au total, 927 participants ont et e admis, dont 37,8% avaient au moins une indication de TDM, la plus fr equente etant une r eponse lente au traitement de la TB (202/345; 58,6%); 55,5% avaient au moins une cavit e pr esente a la radiographie thoracique.Les patients pour lesquels le TDM etait indiqu e sont rest es a l'hôpital pendant une dur ee m ediane de 67 jours et ont mis en moyenne 2 mois de plus pour obtenir une issue favorable a la TB.C O N C L U S I O N : Le TDM pourrait être un outil pr ecieux pour am eliorer la prise en charge de certains patients tuberculeux.La d ecision d'effectuer ou non un TDM est souvent retard ee de deux mois en raison de l'attente des r esultats de la culture apr es le d ebut du traitement.Un essai contrôl e randomis e devrait être r ealis e afin de d efinir le rôle pr ecis du TDM dans le traitement de la TB.
The International Journal of Tuberculosis and Lung Disease i

Figure
Figure Number of patients who had guideline indications for TDM.Slow response to tuberculosis treatment -culture conversion beyond month 2 for drug-susceptible TB and 4 months for drug-resistant TB despite adherence; severe gastro-intestinal abnormalities -severe gastroparesis, short bowel syndrome, chronic diarrhoea with malabsorption; Impaired renal clearance -CKD at least Stage 4 (eGFR < 30 ml/min/1.73m 2 , CKD Epidemiology Collaboration) or acute kidney failure (drop in eGFR of at least 50%).TDM ¼ therapeutic drug monitoring; CKD ¼ chronic kidney disease; eGFR ¼ estimated glomerular filtration rate.
Le suivi th erapeutique des m edicaments (TDM) pourrait am eliorer les r esultats du traitement de la TB en evitant la toxicit e des m edicaments ou le sousdosage.Dans cette etude, nous d ecrivons la charge de travail des patients dans trois centres antituberculeux de Roumanie et d'Ukraine avec une indication de TDM, conform ement aux directives actuelles, afin d'estimer la faisabilit e de la mise en oeuvre du TDM.M É T H O D E S :

Table
Characteristics of patients with TDM indication